TY - JOUR
T1 - Ionizable polymeric micelles (IPMs) for efficient siRNA delivery
AU - Zhou, Ziyu
AU - Feng, Yu
AU - Jiang, Mingzhou
AU - Yao, Zijun
AU - Wang, Jing
AU - Pan, Feng
AU - Feng, Rulan
AU - Zhao, Chong
AU - Ma, Yinyu
AU - Zhou, Jinge
AU - Sun, Lei
AU - Sun, Xiaotian
AU - Zhan, Changyou
AU - He, Xiao
AU - Jiang, Kuan
AU - Yu, Jiahui
AU - Yan, Zhiqiang
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.
AB - Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.
UR - https://www.scopus.com/pages/publications/85214142955
U2 - 10.1038/s41467-024-55721-w
DO - 10.1038/s41467-024-55721-w
M3 - 文章
C2 - 39753560
AN - SCOPUS:85214142955
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 360
ER -